The invention relates to novel steroid derivatives and processes and intermediates for the preparation of these compounds.
Some compounds that associate strongly with the outer membrane of Gram-negative bacteria are known to disrupt the outer membrane and increase permeability. The increased permeability can increase the susceptibility of Gram-negative bacteria to other antibiotics. The best studied of this type of compound are the polymyxin antibiotics. For an example of a study involving the binding of polymyxin B to the primary constituent of the outer membrane of Gram-negative bacteria (lipid A) see: D. C. Morrison and D. M. Jacobs, Binding of Polymyxin B to The Lipid a Portion of Bacterial Lipopolysaccharides, Immunochemistry 1976, vol. 13, 813-819. For an example of a study involving the binding of a polymyxin derivative to Gram-negative bacteria see: M. Vaara and P. Viljanen, Binding of Polymyxin B Nonapeptide to Gram-negative Bacteria, Antimicrobial Agents and Chemotherapy, 1985, vol. 27, 548-554.
Membranes of Gram-negative bacteria are semipermeable molecular “sieves” which restrict access of antibiotics and host defense molecules to their targets within the bacterial cell. Thus, cations and polycations which interact with and break down the outer membrane permeability barrier are capable of increasing the susceptibility of Gram-negative pathogenic bacteria to antibiotics and host defense molecules. Hancock and Wong demonstrated that a broad range of peptides could overcome the permeability barrier and coined the name “permeabilizers” to describe them (Hancock and Wong, Antimicrob. Agents Chemother., 26:48, 1984).